Gut transplantation is now clinical reality, but multiple unexplained problems with enteric function (motility, absorption) exist. The LONG-TERM GOAL of this program is to understand enteric function of the transplanted gut. Because gut transplantation necessitates denervation with "neural isolation" of the transplanted segment from the remaining gut and from the CNS, our research approach (NIH funded since 1989) has been that before we can understand function of allografted gut (subject to the spectrum of immune phenomena), we must first understand enteric function of denervated gut and mechanisms involved in its pathophysiology. The proposal is divided into 2 parts, Part A- Motility and Part B-Absorption, and uses an integrative in vivo approach to study physiologic mechanisms in the whole animal using specific models of surgical denervations and transplantation and directed approaches to study mechanisms using selected in vitro techniques (smooth muscle contractility, brush border membrane transport, morphology, etc). The SPECIFIC AIMS study mechanisms by which extrinsic innervation to the gut controls A1) initiation/coordination of gastric and duodenal motility, A2) global motor patterns and local contractile characteristics of the ileum, A3) proximal colonic motor activity and tone (reservoir function), B1) jejunal and ileal adaptation in absorptive function after massive small bowel resection, and B2) colonic absorptive function. Specific aims A1, A3, and B2 address clinically relevant scenarios of multivisceral gut transplantation (stomach, small bowel and colon), A2 addresses isolated small bowel transplantation, and B1 models living-related segmental small bowel transplantation. Specific aim A4 focuses on extrinsic and intrinsic neural control of smooth muscle contractility by study of smooth muscle in vitro from jejunum and ileum after isogeneic transplantation (inbred rats) devoid of confounding immune phenomena. This latter aim builds on past and ongoing work in the whole animal. This proposal will define important new neural (and hormonal) mechanisms regulating motor and absorptive function in denervated gut. Selected aspects are pertinent to clinical gut transplantation.